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•Acalabrutinib has a favorable benefit-risk profile, including lower incidence of cardiovascular-related toxicities, vs ibrutinib.•AE burden score allowed further comparison of the safety of acalabrutinib vs ibrutinib accounting for AE duration, recurrence, and grade.

The mechanisms of coordinated changes in proteome composition and their relevance for the differentiation of neutrophil granulocytes are not well studied. Here, we discover 2 novel human genetic defects in signal recognition particle receptor alpha (SRPRA) and SRP19, constituents of the mammalian cotranslational targeting machinery, and characterize their roles in neutrophil granulocyte differentiation. We systematically study the proteome of neutrophil granulocytes from patients with variants in the SRP genes, HAX1, and ELANE, and identify global as well as specific proteome aberrations. Using in vitro differentiation of human induced pluripotent stem cells and in vivo zebrafish models, we study the effects of SRP deficiency on neutrophil granulocyte development. In a heterologous cell–based inducible protein expression system, we validate the effects conferred by SRP dysfunction for selected proteins that we identified in our proteome screen. Thus, SRP-dependent protein processing, intracellular trafficking, and homeostasis are critically important for the differentiation of neutrophil granulocytes.

Introduction:T cell lymphomas (NHL-T) account for 10-15% of all non-Hodgkin lymphomas (NHL). They are a heterogeneous group of infrequent neoplasms with a variable clinical course but prevalently aggressive behavior and high mortality rates. Diagnosis is still challenging and there has been little change in the overall prognosis over the last two decades. In spite of IPI (International Prognostic Index) that include extranodal (EN) site in its variables, lack is known regarding EN involvement in nodal peripheral T cell lymphomas- PTCL (PTCL-NOS, TFH and ALCL ALK+/ALK-) location or impact on prognosis).

INTRODUCTION: Peripheral T-cell lymphomas (PTCL) represent a rare and heterogenous group of mature T-cell lymphomas often characterized by aggressive behavior. Previous studies evaluating the distribution of PTCL subtypes across Latin America (LATAM) were limited in their representation of most countries in the region. Additionally, a lack of standardized management for several subtypes and the absence of comprehensive lymphoma registries in LATAM suggests exploring real-world treatment patterns and clinical outcomes. We conducted an international pooled analysis to assess the distribution of PTCL across LATAM countries and report treatment outcomes.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/locate/withdrawalpolicy).

Background

BACKGROUND

INTRODUCTION:Methotrexate is a fundamental drug in the treatment of acute lymphoblastic leukemia (ALL), playing an important role in CNS prophylaxis. Two strategies of methotrexate intensification have been studied: high-dose regimens (with leucovorin salvage) and Capizzi regimen (escalating doses, without salvage, with addition of L-asparaginase). Fifty-five percent of pediatric patients with ALL in Mexico are treated in general hospitals, with limited hospital bed availability, which may represent a deferral of treatment. We wanted to explore a feasible, economical and accessible ambulatory scheme, which may represent an option for those centers that do not have the infrastructure for maintenance with HDMTX.

Thrombocytopathy is the most likely diagnosis for patients with easy bruising and/or mucous bleeding and normal platelet counts. However, in a small proportion of these patients, all hemostatic tests are normal and the right diagnosis is actually Ehlers-Danlos syndrome (EDS). EDS is a heterogeneous group of genetic connective tissue disorders, characterized by joint hypermobility, skin and vascular fragility, and tissue friability; the most recent classification describes 13 clinical subtypes of EDS with mutations in 19 different genes (Malfait et al. Am J Med Genet C Semin Med Genet. 2017;175:8). Besides joint hypermobility, cutaneous-mucosal bleeding of variable intensity is observed in the majority of patients. In the vascular subtype of EDS, arterial aneurysms, dissections and ruptures of arteries and arteriovenous fistulas are detected as manifestations of vascular fragility; less frequently, such vascular pathologies can also appear in other types of EDS (Malfait. Matrix Biol 2018;71-72:380).

Duration of previous treatment, duration and depth of molecular response, previous resistance, BCR::ABL1transcript, and lymphocyte subtypes are known predictive factors of molecular recurrence after tyrosine kinase inhibitors (TKI) discontinuation in chronic myeloid leukemia (CML) patients (pts). Few studies explored the kinetics of BCR::ABL1during a dose de-escalation phase before discontinuation in predicting molecular relapse.

Despite evolution of therapeutic strategies, there is no universal standard of care for relapsed or refractory (RR) mature T and NK-cell neoplasms (TNKL). Most patients receive multiple lines of therapy and cycle through many available options. 1-3There is no data to inform optimal therapy sequence, however emerging data suggest that exposure to epigenetic modifiers (EM) can sensitize tumors to other therapies. 4-6Here we report results of comparative analyses assessing survival outcomes based on therapy sequence using a global RR TNKL patient cohort with data from 15 centers across 6 continents.

Background: Chimeric antigen receptor T-cell (CAR-T) therapy has become a viable treatment option for patients (pts) with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL). Transcriptomic markers for CD19 directed CAR-T failure have been characterized in pre-treatment B-cell acute lymphoblastic leukemia (B-ALL) but not in DLBCL. Here, we report the identification of RNA alternative splicing (AS) events associated with CD19 directed CAR-T response in pre-treatment DLBCL pts and of RNA binding proteins (RNABP) regulating these AS events.

Sickle cell disease (SCD) is a life-threatening genetic condition arising from a point mutation in the β-globin gene that causes hemoglobin polymerization and vaso-occlusive sickling of erythrocytes. Hereditary persistence or pharmacologic induction of gamma-globin (HBG1 or HBG2) expression leads to increases in fetal hemoglobin (HbF) that biophysically oppose hemoglobin polymerization. Indeed, the standard-of-care, hydroxyurea (HU), increases expression of HbF in the erythroblast, and in patients the magnitude of response (9-24% HbF) correlates with a reduction in pain crises and acute complications. However, the use of HU is limited by variable response, myelosuppression, GI side effects and carcinogenicity risk.

Background:Ibrutinib, the first Bruton tyrosine kinase inhibitor (BTKi) indicated for CLL, has been associated with a higher risk of CV events, including atrial fibrillation (AF) and hypertension, vs non-BTKi active comparators and placebo. In a phase 3 clinical trial of patients (pts) with CLL comparing ibrutinib with acalabrutinib-a more selective, second-generation BTKi-CV event incidence was numerically higher with ibrutinib and the incidence and cumulative risk of AF were significantly higher with ibrutinib (Byrd JC et al. J Clin Oncol. 2021;39:3441-52). Ibrutinib's toxicity profile prompted changes to its prescribing information and lowered its recommendation status in current CLL guidelines. We conducted an SLR of interventional trials in CLL followed by a supplemental TLR of observational studies in CLL to explore the extent to which CV outcomes of pts with CLL are driven by their baseline comorbidities or treatments.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/locate/withdrawalpolicy).

Background:Autologous chimeric antigen receptor (CAR) T-cell therapy is standard of care for patients with relapsed or refractory Large B cell Lymphoma (R/R LBCL). Each patient's CAR T product is unique, and the patient-specific determinants of CAR T-cell quality are poorly understood. CD39 is an ectonucleosidase that participates in the conversion of ATP and ADP and is upregulated in cancer. On T-cells, CD39 is expressed on CD4+ Tregs and on exhausted CD8+ T-cells that are prone to apoptosis.

Acute myeloid leukemia (AML) and myelodysplasia (MDS) result from a differentiation impairment driving an accumulation of immature myeloid cells in the bone marrow and peripheral blood. A widely reported feature of these neoplastic myeloid cells is an increased cell surface expression of CD123, the IL3 receptor α subunit. This observation has established CD123 as an attractive target for precision therapy. Here, we describe BYON4413, a novel antibody-drug conjugate (ADC) that binds with high affinity to CD123. BYON4413 comprises a humanized IgG1 antibody directed at CD123 that is site-specifically conjugated to Byondis' proprietary duocarmazine linker-drug (LD) technology, ByonZine® and ByonShieLD®. This LD, when cleaved upon internalization and lysosomal routing, releases a potent duocarmycin payload that alkylates DNA, generating damage that results in replication stress and cell death. In vitrostudies with AML cell lines demonstrate that BYON4413 is highly effective in eradicating CD123-positive cells while having little impact on CD123-negative cells. Similar results are observed when we test BYON4413 on AML patient-derived BMMCs/PBMCs in ex vivoassays (n=50), indicating that the specificity of BYON4413 cytotoxicity is largely limited to CD123-positive cells. Ex vivoexperiments also reveal a stronger potency of BYON4413 in AML patient-derived blasts compared to healthy CD34 +hematopoietic stem/progenitor cells. In vivoPK/PD studies demonstrate that BYON4413 is remarkably efficient at reducing the tumor burden in multiple AML patient- and cell line-derived xenograft models. Studies in non-human primates suggest that BYON4413 has a favorable toxicity profile and a high maximum tolerable dose, features that should enable combination strategies with other oncolytics. In sum, BYON4413 shows great potential to be an effective targeted therapy against AML, MDS, and other CD123 +hematological malignancies such as blastic plasmacytoid dendritic cell neoplasm (BPDCN). Readied with these promising pre-clinical results, we have designed a first-in-human dose-escalation and expansion trial enrolling AML and high-risk MDS patients scheduled to begin in Q12024.

Introduction: Despite advances in the treatment of hematologic malignancies (HM), a significant number of patients still present with high burden of symptoms, and many still die from their diseases. Adequate integration of palliative care (PC) shows strong potential to improve quality of life of this population. However, PC strategies are underutilized due to several barriers in the context of high prognosis uncertainty. Therefore, it is crucial to implement practical tools and triggers for opportune discussions concerning goals of care and specialist PC consultations. The “Surprise-Question” (SQ) “Would you be surprised if this patient died in the next 12 months?” is a simple and feasible instrument for intuitive estimation of mortality among patients with different types of advanced disease with the aim to improve prognostic awareness among healthcare professionals. In 2016 this instrument was introduced in the American Society of Clinical Oncology (ASCO) Integration of Palliative Care Into Standard Oncology Care Guideline. Most studies refer the SQ to solid tumors and very little is known about the application of this tool in the context of HM. We evaluated the prognostic performance of the SQ among patients with HM.

Background

Introduction

Background

Introduction

Introduction

Immunoglobin light chain amyloidosis (AL) is a monoclonal gammopathy characterized by the accumulation of malignant plasma cells (PC) in the bone marrow. These PCs secrete misfolded immunoglobulin light chains fibrils, which deposit in various organs, leading to organ dysfunction. Unlike other monoclonal gammopathies such as Multiple Myeloma, both its rarity and the lower BM PC burden has limited the deep study of the tumor population. The aim of this study was to analyze the transcriptome and epigenome of the PC from patients with AL amyloidosis to identify the role of chromatin modifications in the pathogenesis of the disease.

Introduction:Chronic psychosocial stress has been linked to cancer development and progression. Allostatic load (AL) has been proposed as a novel approach to measure the biological consequence of cumulative stress seeking to explain health disparities. As a multidimensional framework, AL delineates functioning across several physiologic networks including neuroendocrine, cardiovascular, metabolic, and inflammatory systems. Emerging evidence highlights the association between AL and cancer risk, yet little is known about its relevance in hematologic malignancies and its impact on treatment outcomes.

Background

Background: In myelodysplastic syndromes (MDS), defects occur at multiple stages of hematopoiesis. Available Erythropoiesis Stimulating or Erythroid Maturation Agents (ES/EMAs) target early or late stages of erythropoiesis, respectively, and are only effective in subsets of patients. For patients with high transfusion burden (HTB) who have diminished erythropoietic capacity and a worse prognosis, ES/EMAs show limited efficacy and durability of response (DOR). KER-050 is an investigational, modified activin receptor type IIA ligand trap designed to inhibit select TGF-β superfamily ligands (activins A, B, GDFs 8, 11) that is being evaluated in diseases with ineffective hematopoiesis (IH), including MDS and myelofibrosis. Preclinical studies demonstrated that KER-050 increased erythropoiesis and thrombopoiesis and acted on early- and late-stage erythropoietic and megakaryocyte progenitors. By eliciting effects on hematopoiesis across multiple differentiation stages and cell lineages, KER-050 has the potential to address the complex nature of IH and to provide robust and sustained hematological improvement in patients with MDS who have limited treatment options, including those with HTB or non-ring sideroblast (RS) MDS.

Background:Patients (pts) with CLL have a high rate of comorbidities, including cardiovascular disease (CVD). Comorbid CVD is correlated with higher mortality in this pt population. Hypertension (HTN) is the most common concurrent CVD in pts with CLL and is associated with development of complications such as stroke and heart failure. The incidence of new or worsening HTN in treatment-naive CLL pts receiving placebo within the CLL12 trial was 8.3% over a 69.3-month observation period (Langerbeins et al. Hematol Oncol. 2023). New and/or worsening HTN has been observed in pts with CLL treated with Bruton tyrosine kinase inhibitor (BTKi) therapy. Studies have shown new or worsening HTN with ibrutinib (7−30%) and zanubrutinib (11−20%) (Christensen et al. Expert Rev Hematol. 2022). Acalabrutinib (acala), a selective, second-generation BTKi, demonstrated a lower rate of HTN (8.6%) vs ibrutinib (22.8%) in the head-to-head ELEVATE-RR study at a median follow-up of 40.9 months (Byrd et al. J Clin Oncol.2021). Here, we performed a cumulative analysis of new or worsening HTN from the acala global development program and compared these data against real-world prevalence and incidence of HTN for pts with CLL prior to treatment initiation using claims data.

Multiple Myeloma (MM) is the second most common hematologic neoplasia, and it remains largely incurable due to the genetic heterogeneity of the patients. We have recently characterized the epigenome of plasma cells from patients with MM, describing the de novoactivation of the chromatin as a unifying factor underlying the pathobiology of the MM. Precisely, we identified 1556 de novoactive regions, showing the H3K27ac chromatin activation mark, in MM in comparison to different subpopulations of normal B cells. Moreover, those de novoactive regions where enriched in Transcription Factor Binding Sites (TFBS). In order to defined the potential role of these regions we have performed a CRISPR-Cas9 screening using guides against 56 TF that presented TFBS in de novoactive regions and that are expressed in MM. A CRISPR-Cas9 library containing 10 guides for each gene was transduced in two MM cell lines (MM.1R and KMS-11) and the presences of guides were analyzed at days +1, +14 and +21. Out of the 22 TFs shown to be essential for MM survival, there were 3 members of the IRF TF family (IRF1, IRF2 and IRF5). Single knockdowns identified IRF2 and the previously described IRF4 as the best candidates.

Introduction and aims:Adult acute lymphoblastic leukemia (ALL) is a heterogeneous group of highly aggressive hematological malignancies with high recurrence rates and poor prognosis. Pharmacological inhibition of proteins of the phosphatidylinositol-5-phosphate 4-kinase type 2 family (PIP4K2s), through the compound THZ-P1-2, exhibits antileukemic activity by interrupting mitochondrial homeostasis and autophagy. Nevertheless, different pharmacological inhibitors with distinct affinities for PIP4K2s have been developed (PIP4K-IN-a131 and CC260), but their potential as antileukemic agents has been little explored. In the present study, we investigated the expression of PIP4K2s in ALL patients and cell models. Furthermore, the potency and efficacy of three PIP4K2s inhibitors were characterized in ALL cells.

Background:Acalabrutinib (acala), a second-generation Bruton tyrosine kinase inhibitor (BTKi), with or without obinutuzumab (obin), demonstrated superior progression-free survival (PFS) compared with obin plus chlorambucil in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL) in the phase 3 ELEVATE-TN (NCT02475681) trial. Despite the long-term benefits observed with acala therapy, data from real-world studies in patients with CLL demonstrate that 22% of patients discontinue acala treatment for any reason in the first year of treatment across therapy lines (Roeker et al. Blood.2022). To assess the impact on survival outcomes of acala discontinuation and dose modifications occurring in the first year of treatment, we conducted a post hoc analysis in patients treated in the acala-containing arms of ELEVATE-TN.

Background:The approval of ibrutinib, the first covalent Bruton tyrosine kinase inhibitor (BTKi), provided an effective non-chemotherapy option for the treatment of B-cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). While generally well tolerated, ibrutinib demonstrated significant toxicities in clinical studies, particularly cardiovascular adverse events such as hypertension, atrial fibrillation, and ventricular arrhythmias (VAs). Post hoc analysis of the phase 3 FLAIR trial in patients with previously untreated CLL reported an unexplained sudden or cardiac death rate of 0.5 patients per 100 patient-years with ibrutinib plus rituximab (Hillmen et al. Lancet Oncol. 2023). Acalabrutinib is a next-generation, more selective, irreversible BTKi approved to treat CLL/SLL and relapsed/refractory mantle cell lymphoma. Herein, the rates of nonfatal and fatal VAs and sudden deaths (SDs) from 5 acalabrutinib clinical trials of patients with CLL were analyzed.

Background:Anaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell lymphomas that share pathologic features but differ in clinical presentation, outcome, and molecular features. The World Health Organization (WHO) and International Consensus Classification (ICC) classify ALCLs by presence or absence of ALKrearrangements (R) and clinical presentation (systemic, cutaneous [c], or breast implant-associated [BIA]). ICC, but not WHO, recognizes DUSP22-R as defining a new genetic subtype of ALK- ALCL. The classifications otherwise do not reflect additional molecular heterogeneity in genetics (e.g., TP63-R) or therapeutic vulnerabilities (e.g., JAK-STAT3 pathway activation).

Introduction.Idecabtagene vicleucel (ide-cel) is a chimeric antigen receptor T-cell therapy (CAR-T) approved for patients with triple-class exposed relapsed/refractory multiple myeloma (TCE RRMM) (Munshi NC, et al. N Engl J Med2021;384:705-716). Treatment-related toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are prevalent and common to all CAR T-cell therapies. We examined the association of serum cytokines and pre-CAR-T bone marrow composition with toxicity and early response among patients with TCE RRMM treated with ide-cel.

Introduction and aims:Proteins of the PIP4K2s family (PIP4K2A, PIP4K2B and PIP4K2C) participate in the generation of PIP 4,5P 2(PIP 2), which acts as a secondary messenger in signal transduction, substrate for metabolic processes or has structural functions. In patients with AML, high expression of PIP4K2Aand PIP4K2Cis an independent marker of worse prognosis. Recently, our research group reported that THZ-P1-2 (pan-inhibitor of PIP4K2s) exhibits anti-leukemic activity by disrupting mitochondrial homeostasis and autophagy in AML models. In the present study, we describe the expression profile of PIP4K2s in normal and leukemic myeloid cells, as well as identify the association between PIP4K2s expression and the ex vivoresponse to several antineoplastic agents in AML.

Introduction:Ide-cel is a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy associated with deep and durable responses and improved quality of life among triple-class exposed (TCE) patients with relapsed/refractory multiple myeloma (RRMM) (Munshi NC, et al. N Engl J Med2021;384:705-716; Delforge M, et al. Blood Adv2022;6:1309-1318). An analysis of 2-year post-infusion facility-related HCRU (fHCRU) associated with ide-cel treatment in the phase 2 KarMMa clinical trial (NCT03361748) found that most facility costs were incurred within the first month following infusion where the median hospital length of stay (LOS) was 19.5 days which included the clinical trial requirement of hospitalization for monitoring and 20% of the patients had intensive care unit (ICU) stays (McGarvey N, et al. Blood2022;140(suppl 1):10947-10948). In this study, we estimated fHCRU and associated costs for patients with TCE RRMM receiving ide-cel in RW clinical practice.

There is no universal approach to treat patients with relapsed and refractory (RR) mature T-cell and NK-cell neoplasms (TNKL). While participation in a clinical trial is favored, appropriate options are often unavailable. Thus, outside of a trial, physicians may rely on real world evidence when making a treatment choice. We hypothesized that innovative causal predictive models that utilize existing clinical information could estimate comparative efficacy of various treatments and support clinical decision making.